ADAM metallopeptidase domain 17 (ADAM17) is naturally processed through major histocompatibility complex (MHC) class I molecules and is a potential immunotherapeutic target in breast
Background Zoledronic acid (ZA) in combination with endocrine therapy (ET) and ovarian ablation (OA) reported a DFS advantage in premenopausal women with early stage breast cancer (EBC) in ABCSG-12. Emerging evidence from pre-clinical studies suggests that ZA increases gamma/delta T-cells (GDT), an immune cell population with anti-tumor activity. This study examined immune responses to a single dose of ZA in patients with either EBC or metastatic breast cancer (MBC) through sequential measurement of T-cells and immune regulatory cytokines.
Methods Women with EBC/MBC, both pre- and post-menopausal, and no history of immune dysregulation who were scheduled to receive their first-ever dose of ZA were eligible. Blood was collected for serum and blood mononuclear cells at Day 0 (pre-ZA), Day 1 (18-48 hours post-ZA), Day 7 (Day 5–8 post ZA), and Day 28 (Day 25–32 post-ZA). GDT populations and cytokine responses were assayed using flow cytometry and multi-analyte profiling beads (Luminex), respectively. Relative changes from baseline at days 1, 7 and 18 were quantified using log-ratios and analyzed using the Wilcoxon signed-rank test.
Results 24 patients were enrolled from Oct 2009 to Mar 2011. 75% of pts had MBC, and 25% had EBC, while 75% received ET, 17% received chemo (C), and 8% received other. Following ZA administration, a transient decrease in total GDT (CD3+/Vdelta2+) at Day 1 was seen (p<0.0003). This was followed by an increase in both effector (CD3+/Vdelta2+/CD45RA-/CD27-) (P<0.005) and central memory GDT (CD3+/Vdelta2+/CD45RA-/CD27+)(P<0.007) and a decrease in naïve GDT (CD3+/Vdelta2+/CD45RA+/CD27+) (P<0.006) at day 7; total GDT unchanged. The change in naïve GDT and effector GDT appeared to persist at Day 28. IL-1RA (P<0.003), IL-12 (P<0.0005), MIP-1b (P<0.0005), IP-10 (P<0.00002) and MIG (P<0.00006), were increased at Day 1 compared to baseline. By day 28, these cytokine levels returned to baseline except IP-10 which appeared to remain elevated. In this limited patient sample, no differences were observed between patients with EBC vs. MBC, ET vs. C, and pre- vs. post-menopausal.
Conclusion: ZA appears to induce a highly significant change in immune effector cells in both EBC and MBC patients receiving ET or C. Mobilization of anti-tumor T-cells with a decrease in total (non-specific) GDT followed by a marked increase post-ZA in specific central and effector memory GDT was seen at day 7. Significant increases in cytokine levels, like those seen in this study including those associated with Th1 responses or cell-mediated immunity, as well as IL-12 levels, have been implicated in direct anti-tumor activity. This apparent cytokine and cellular response to ZA could offer an important biologic mechanism for the anti-cancer activity reported in ABCSG-12. Further studies should be performed to determine which subsets of BC patients might achieve these described immune benefits from ZA.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-13-03.
Background: Immune-based therapy for metastatic breast cancer has had limited success. Strategies to augment adaptive immunity include vaccines targeting genomic amplifications like Human Epidermal Growth Factor Type 2 (HER2), an established driver of malignancy. Using a novel alphaviral vector, we constructed a vaccine encoding a portion of HER2 (VRP-HER2).
Methods: In preclinical studies, mice were immunized before or after implantation of hHER2+ tumor cells and HER2-specific immune responses and anti-tumor function were assessed. We then translated this vaccine into a phase I clinical trial in which subjects with advanced HER2-overexpressing breast cancers received VRP-HER2 every 2 weeks for a total of three doses (cohort 1). In cohort 2, subjects received the same dose of VRP-HER2 along with a standard HER2 targeted therapy.
Results: VRP-HER2 induced HER2-specific T cell and antibody responses while controlling tumor growth in murine models. Vaccination with VRP-HER2 was well tolerated in both patient cohorts. PFS was modest, while median OS was 50.2 months in cohort 1 and 32.7 months in cohort 2. In cohort 2, there is one partial response and two patients with continued stable disease. Vaccine induced anti-HER2 antibodies and T cells were identified. Increased perforin expression by memory CD8 T cells post vaccination significantly correlated with improved PFS.
Conclusions: VRP-HER2 led to an increase in perforin expressing HER2-specific memory CD8 T cells in preclinical and clinical studies, and had profound antitumor effects in murine models. The generation of HER2-specific memory CD8 T cells was significantly correlated with increased PFS in patients. Subsequent studies will seek to enhance T cell activity by combination with anti-PD-1/PD-L1 antibodies.
Citation Format: Crosby EJ, Gwin WR, Chang S, Maecker HT, Lubkov V, Snyder JC, Broadwater G, Hyslop T, Osada T, Hobeika AC, Hartman ZC, Morse MA, Lyerly HK. CD8 T cells induced by novel alphaviral vector predict improved progression free survival in advanced HER2+ breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-09-16.
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